The therapeutic pipeline for nonalcoholic steatohepatitis (NASH) is expanding as insights into disease pathophysiology are gained. This Review summarizes progress in the development of NASH therapies, current and ongoing clinical trials, and potential challenges with emerging therapies.
NAFLD and NASH
Fuelled by increasing obesity rates, NAFLD has emerged as a leading global cause of chronic liver disease in the past few decades. Despite growing prevalence, the factors influencing NAFLD development and subsequent progression to NASH, liver fibrosis, cirrhosis and hepatocellular carcinoma are poorly understood. In this article series, Nature Reviews Gastroenterology & Hepatology explores the epidemiology of NAFLD, disease mechanisms and therapeutics, and clinical aspects including screening, diagnosis and management.
Reviews and Perspectives
The prevalence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is projected to continue to increase worldwide. In this Review, Huang, El-Serag and Loomba discuss the global epidemiology and risk factors for NAFLD-related HCC, and propose strategies to tackle this problem.
This Review describes the pathophysiological roles of peroxisome proliferator-activated receptors (PPARs) in nonalcoholic steatohepatitis and related metabolic diseases, and summarizes the preclinical and clinical data on the use of PPAR agonists to treat nonalcoholic steatohepatitis as part of a systemic metabolic disease.
Emerging data have revealed that nonalcoholic steatohepatitis (NASH) and fibrosis are associated with the reactivation of developmental pathways in the liver injury response. This Review describes the role of these pathways in liver development and in the pathogenesis of NASH and fibrosis.
The gut microbiota has been linked to non-alcoholic fatty liver disease (NAFLD), but metabolic confounding factors, such as obesity and diabetes, complicate analysis. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling them from underlying metabolic disorders.
This Review discusses the genetics of nonalcoholic fatty liver disease (NAFLD), including evidence of shared genetic modifiers and possible pleiotropic effects between NAFLD and other liver diseases or metabolic disorders. The translational implications and future challenges are also discussed.
Innate immune responses are currently seen as a key element driving hepatic inflammation in nonalcoholic steatohepatitis. However, this Review discusses the increasing evidence pointing to the role of adaptive immunity as an additional factor promoting liver inflammation and driving disease progression.
Nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in children and adolescents. In this Review, the authors summarize current knowledge and new advances related to the epidemiology, pathogenesis and management of paediatric NAFLD.
The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), underlies many cases of hepatocellular carcinoma (HCC). In this Review, the authors discuss NAFLD-associated HCC, including its epidemiology, key features that promote hepatocarcinogenesis and the management of HCC in patients with obesity.
Nonalcoholic fatty liver disease (NAFLD) was first described four decades ago, but it is increasingly important owing to its high prevalence in the general population. This Perspective provides an overview on the development of knowledge related to NAFLD, focusing on landmark findings.
The liver is a key metabolic organ, and alterations to hepatic metabolism are important for the development of disease. In this Review, the authors explore the central roles of peroxisome proliferator-activated receptor-γ coactivators (PGC1s) in physiological and pathophysiological settings, with a focus on nonalcoholic fatty liver disease and liver cancer.
The pathophysiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis is not yet completely understood but innate immunity is a major factor. In this Review, the evidence for macrophage involvement in the development of liver steatosis, inflammation and fibrosis is discussed.
The combination of increasing disease prevalence and the prospect of approved pharmacological treatments has made the development of noninvasive biomarkers for NAFLD and NASH a research priority. In this Review, the authors comprehensively summarize the features of current and potential biochemical, imaging and genetic biomarkers.
Nonalcoholic steatohepatitis is the progressive form of nonalcoholic fatty liver disease, one of the most common chronic liver diseases. In this Review, the authors comprehensively discuss the key factors that trigger hepatic inflammation, as well as the pathways involved in inflammation resolution.
Cardiovascular disease is the leading cause of death in NAFLD. In this Review, the authors explore the evidence that NAFLD affects not only the coronary arteries but also all other cardiac structures, thereby potentially increasing risk of cardiomyopathy, cardiac arrhythmias, conduction defects and valvular calcification.
Elastography is the most accurate noninvasive approach to assess liver fibrosis in patients with NAFLD. Here, the authors discuss the benefits and limitations of various elastographic modalities, their role in the optimal management of NAFLD and directions for future research.
NAFLD is growing in prevalence worldwide, and has emerged as a leading cause of end-stage liver disease in many countries. In this Review, the authors describe the global epidemiology of NAFLD, discuss associated risk factors and outline challenges for screening and management.
The association between NAFLD and diabetes mellitus has garnered increasing attention in the past few years. In this Review, Tilg and colleagues explore in detail the molecular mechanisms linking NAFLD and diabetes mellitus, and discuss clinical aspects arising from the interaction of both diseases.
This Review discusses the mechanisms via which changes in the gut can influence the development and progression of NAFLD. Understanding of such mechanisms is hoped to pave the way for new treatments for what has become the most common form of liver disease.
Related news and commentaries
In 2020, there have been substantial advances in nonalcoholic fatty liver disease mechanisms, diagnostics and treatment. Key developments include the identification of a cellular and tissue signature to provide new insights into pathophysiology, advancements in non-invasive diagnostics and publication of interim results of the first phase III trial to demonstrate improvement in hepatic fibrosis.
On ‘International NASH Day’, we launch a call for the global health community to collaboratively shape and deliver a comprehensive, long-term public health agenda for NAFLD. A global multidisciplinary coalition is needed to guide our response to this increasingly prevalent, yet underaddressed disease.
Two new position papers convincingly propose that nonalcoholic fatty liver disease needs a new name — metabolic associated fatty liver disease (MAFLD). A new name for this disease affecting nearly one billion people globally is overdue, as knowledge gained from the past decades has assuringly demonstrated that MAFLD is a purely metabolic disorder.
Advances have been made in the field of nonalcoholic fatty liver disease in 2019. One paper highlights the role of gut microbiota in hepatocellular carcinoma (HCC) pathogenesis, another presents a noninvasive algorithm for detecting advanced liver fibrosis and another suggests a potential novel approach to treating nonalcoholic steatohepatitis and suppressing HCC development.
The diagnostic reach of nonalcoholic fatty liver disease (NAFLD) is broad, stretching from simple steatosis to cirrhosis. Expanded disease definitions are an important cause of waste in health care. Now is the time to revise the definition of NAFLD to include only those who have developed advanced fibrosis.
In 2018, there have been substantial advances in our understanding of the risk factors for advanced liver disease in nonalcoholic fatty liver disease, including genetic variants and the gut microbiota. Promising results have also arisen from drugs targeting metabolic pathways involved in the progression of liver damage.
NAFLD, the hepatic manifestation of the metabolic syndrome, is a multifactorial condition — environmental factors influence an inherited genetic risk. Stender et al. now describe the additive effect of obesity and NAFLD-associated genetic polymorphisms on steatosis, elevated serum alanine aminotransferase levels and cirrhosis, remarkably illustrating the principle of gene–environment interactions.
Currently, no pharmacological therapies are approved for the treatment of NASH. A new study now identifies CASP8 and FADD-like apoptosis regulator (CFLAR) as a novel suppressor of NASH and its associated disorders in a process dependent on the activation of apoptosis signal-regulating kinase 1 (ASK1).
In a new study, Younossi et al. poignantly depict the daunting and enormous prevalence of NAFLD and its associated clinical and economic burden in the USA and four countries in Europe. The astronomical health-care costs will increase as the prevalence of NAFLD increases. All stakeholders are called to action.
A recent study reports that being overweight in late adolescence is associated with an increased risk of liver-related morbidity and mortality later in life. These findings give further strength to the concerns for the deleterious effects of childhood obesity on liver health. Early prevention by screening and lifestyle modification should be advised by health policies.